Escherichia coli α-hemolysin counteracts the anti-virulence innate immune response triggered by the Rho GTPase activating toxin CNF1 during bacteremia.
Escherichia coli α-hemolysin counteracts the anti-virulence innate immune response triggered by the Rho GTPase activating toxin CNF1 during bacteremia.
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DOI：
10.1371/journal.ppat.1004732
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发表时间：
2015-03
期刊：
影响因子：
6.7
通讯作者：
Boyer L
中科院分区：
文献类型：
--
作者：
Diabate M;Munro P;Garcia E;Jacquel A;Michel G;Obba S;Goncalves D;Luci C;Marchetti S;Demon D;Degos C;Bechah Y;Mege JL;Lamkanfi M;Auberger P;Gorvel JP;Stuart LM;Landraud L;Lemichez E;Boyer L
通过先天免疫系统检测病原体编码的毒力因子的活性已成为病原体识别的新范式。关于哺乳动物中有助于这种防御机制的分子和细胞成分以及在感染期间的重要性，仍有许多问题有待确定。在这里，我们揭示了IL-1β信号轴和Gr 1+细胞在控制血液中大肠杆菌负荷中的核心作用，以响应Rho GTP酶激活毒素CNF 1的传感。一致地，这种先天性免疫应答在半胱天冬酶-1/11受损的小鼠中或在用IL-1β拮抗剂治疗感染的小鼠后被消除。体外实验进一步揭示了CNF 1和LPS在促进IL-1β成熟/分泌方面的协同作用，并确定了Rac、ASC和caspase-1在该途径中的作用。此外，我们发现α-溶血素毒素抑制IL-1β分泌，而不影响Gr 1+细胞的募集。在这里，我们报告的第一个例子，抗毒力引发的免疫力抵消了孔形成毒素在菌血症。大多数微生物的致病潜力取决于一系列毒力因子。尽管在理解细菌效应子活动的分子机制方面取得了重大进展，但对它们在感染期间如何合作克服宿主免疫防御和促进微生物持久性知之甚少。在这里，我们研究了两个尿路致病性大肠杆菌（UPEC）的作用，协同表达，α-溶血素（HlyA）和细胞毒性坏死因子1（CNF 1）。我们证明了HlyA毒素对血液中细菌的稳定性至关重要，并表明HlyA的一个重要作用是抑制CNF 1诱导的宿主反应。总的来说，这些发现揭示了为什么HlyA和CNF 1的协调活性对于UPEC的完全毒力是必要的。此外，它们解开了细菌用来促进其生存的HlyA驱动的反防御机制。
The detection of the activities of pathogen-encoded virulence factors by the innate immune system has emerged as a new paradigm of pathogen recognition. Much remains to be determined with regard to the molecular and cellular components contributing to this defense mechanism in mammals and importance during infection. Here, we reveal the central role of the IL-1β signaling axis and Gr1+ cells in controlling the Escherichia coli burden in the blood in response to the sensing of the Rho GTPase-activating toxin CNF1. Consistently, this innate immune response is abrogated in caspase-1/11-impaired mice or following the treatment of infected mice with an IL-1β antagonist. In vitro experiments further revealed the synergistic effects of CNF1 and LPS in promoting the maturation/secretion of IL-1β and establishing the roles of Rac, ASC and caspase-1 in this pathway. Furthermore, we found that the α-hemolysin toxin inhibits IL-1β secretion without affecting the recruitment of Gr1+ cells. Here, we report the first example of anti-virulence-triggered immunity counteracted by a pore-forming toxin during bacteremia. The pathogenic potentials of most microbes depend on a repertoire of virulence factors. Despite major progress in the understanding of the molecular mechanisms underlying the activities of bacterial effectors, little is known about how they cooperate during infection to overcome host immune defenses and promote microbial persistence. Here, we investigated the roles of two uropathogenic Escherichia coli (UPEC) effectors that are co-ordinately expressed, α-hemolysin (HlyA) and cytotoxic necrotizing factor 1 (CNF1). We demonstrated that the HlyA toxin is critical for bacterial stability in the blood and showed that one important role of HlyA is to inhibit the CNF1-induced host response. Collectively, these findings reveal why the coordinated activities of HlyA and CNF1 are necessary for the full virulence of UPEC. Moreover, they unravel a HlyA-driven counter-defense mechanism used by bacteria to facilitate their survival.
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影响因子：
11.3
作者：
Hannan TJ;Totsika M;Mansfield KJ;Moore KH;Schembri MA;Hultgren SJ
通讯作者：
Hultgren SJ
影响因子：
8.7
作者：
Broz P;Monack DM
通讯作者：
Monack DM
影响因子：
6.7
作者：
Bruno VM;Hannemann S;Lara-Tejero M;Flavell RA;Kleinstein SH;Galán JE
通讯作者：
Galán JE
影响因子：
9.4
作者：
CAPRIOLI, A;FALBO, V;DONELLI, G
通讯作者：
DONELLI, G
Interleukin-1家族：回到未来。
影响因子：
32.4
作者：
Garlanda C;Dinarello CA;Mantovani A
通讯作者：
Mantovani A